1. Field of the Invention
This invention relates to a transdermal therapeutic system containing tulobuterol hydrochloride, which system enables the administration of the bronchodilator tulobuterol via the skin. The transdermal medicinal preparation is suitable for treatment of asthmatic diseases.
2. Description of the Related Art
Tulobuterol is a medicinal agent from the group of the β-sympathomimetics. It is predominantly active on the β2-receptors of non-striated muscles, for example, in the bronchi. Due to its having the properties of reducing the bronchial muscular tone and effecting a relaxation of the bronchial muscles, tulobuterol is being used in the therapy of asthmatic diseases.
Apart from oral administration forms, from the literature there are also known transdermal application systems for tulobuterol which can be successfully utilized in asthma therapy. Transdermal therapeutic systems containing tulobuterol have been described, for example, in JP 63-10716 A, U.S. Pat. No. 5,254,348, U.S. Pat. No. 5,312,627, U.S. Pat. No. 5,571,536 and U.S. Pat. No. 5,639,472.
U.S. Pat. No. 5,254,348 discloses a transdermal therapeutic system the tulobuterol-containing matrix of which is built-up on the basis of a styrene-1,3-diene-styrene block copolymer or a styrene-isoprene-styrene block copolymer.
U.S. Pat. No. 5,312,627 describes a transdermal therapeutic system suitable for administering active substances having bronchodilatory action, e.g. tulobuterol. As a matrix polymer, polyisobutylene is used.
In U.S. Pat. No. 5,571,530 there is likewise described a percutaneous composition comprising the active substance tulobuterol, with the active substance being present in a polymer matrix made up of a mixture of polyisobutylenes.
From U.S. Pat. No. 5,639,472 there is known a tulobuterol-containing composition suitable for percutaneous absorption. It is characterized by the fact that tuloburetol is present both in dissolved as well as in crystalline form in the pressure-sensitive adhesive layer of the plaster.
Finally, in EP 0 922 453 A2 there is disclosed a device for the percutaneous administration of tulobuterol. This administration form comprises a pressure-sensitive adhesive acrylate layer containing at least 5%-wt. of tulobuterol as free active substance base in completely dissolved condition. The active substance remains dissolved so that there is no loss of action by crystallization.
A suggestion as to the possible use of salts of tulobuterol or even of the hydrochloride is not found in EP 0 922 453 A2.
In the above-described tulobuterol-containing transdermal therapeutic systems, tulobuterol is preferably utilized as a free base, the reason for this being that the free base on account of its hydrophobic character can be readily absorbed via the skin, whereas the salts of tulobuterol (e.g. tulobuterol hydrochloride) are more strongly hydrophile, which results in a poorer ability to penetrate the skin. For this reason tulobuterol hydrochloride has heretofore only been used for peroral therapy, but not for transdermal administration. Only U.S. Pat. No. 5,254,348 also mentions, in general terms, the pharmaceutically acceptable salts of tulobuterol, without, however, dealing in more detail with the problem of the hydrophilicity or of the poorer capacity for skin penetration of the salts.
Apart from its poorer capacity to penetrate the skin, the use of tulobuterol hydrochloride instead of the free base also affords some remarkable advantages. Firstly, it has been used in asthma therapy for a much longer time and on a far wider scale. This means that one is able to have recourse to considerably more extensive material relating to the toxicology and pharmacology of this active substance. Secondly, due to its being used world-wide on a larger scale, tulobuterol hydrochloride is obtainable on commercially more favourable conditions and from a greater number of sources of supply than the free base. It is also considered an advantage that tulobuterol hydrochloride is monographically described in the Japanese pharmacopoeia (JP XIII). Therefore—by contrast to the case of tulobuterol—there already exists a pharmaceutical quality standard which can be made use of for world-wide approval.